Inverse electron-demand Diels-Alder intermolecular

Intermolecular [4C+2S] cycloaddition reactions where the diene moiety is contained in the carbene complex are less frequent than the [4S+2C] cycloadditions summarised in the previous section. However, 2-butadienylcarbene complexes, generated by a [2+2]/cyclobutene ring opening sequence, undergo Diels-Alder reactions with typical dienophiles [34,35] (Scheme 59). Also, Wulff et al. have described the application of pyranylidene complexes, obtained by a [3+3] cycloaddition reaction (see Sect. 2.8.1), in the inverse-electron-demand Diels-Alder reaction with enol ethers and enamines [87a]. Later, this strategy was applied to the synthesis of steroid-like ring skeletons [87b] (Scheme 59). 

A semiempirical AMI study of the inverse-electron-demand Diels-Alder reaction of 4-substituted 6-nitrobenzofurans with enol ethers and enamines favours a stepwise mechanism involving short-lived diradical intermediates. The inverse-electron-demand intermolecular Diels-Alder reactions of 3,6-bis(trifluoromethyl)-l,2,4,5-tetra-zine with acyclic and cyclic dienophiles followed by the elimination of N2 produce 4,5-dihydropyridazines, which cycloadd further to yield cage compounds. The preparation of jS-carbolines (90) via an intramolecular inverse-electron-demand Diels-Alder... 

The presence or absence of the dioxolane protecting group in dienes dictates whether they participate in normal or inverse-electron-demand Diels-Alder reactions.257 The intramolecular inverse-electron-demand Diels-Alder cycloaddition of 1,2,4-triazines tethered with imidazoles produce tetrahydro-l,5-naphthyridines following the loss of N2 and CH3CN.258 The inverse-electron-demand Diels-Alder reaction of 4,6-dinitrobenzofuroxan (137) with ethyl vinyl ether yields two diastereoisomeric dihydrooxazine /V-oxide adducts (138) and (139) together with a bis(dihydrooxazine A -oxide) product (140) in die presence of excess ethyl vinyl ether (Scheme 52).259 The inverse-electron-demand Diels-Alder reaction of 2,4,6-tris(ethoxycarbonyl)-l,3,5-triazine with 5-aminopyrazoles provides a one-step synthesis of pyrazolo[3,4-djpyrimidines.260 The intermolecular inverse-electron-demand Diels-Alder reactions of trialkyl l,2,4-triazine-4,5,6-tricarboxylates with protected 2-aminoimidazole produced li/-imidazo[4,5-c]pyridines and die rearranged 3//-pyrido[3,2-[Pg.460]

Imidazoles are electron-rich heterocycless and can undergo inverse electron demand Diels-Alder reactions. Particularly, amino-substituted imidazoles are good dienophiles and cyclize with electron-poor counterparts to provide cycloadducts. For example, intermolecular cycloadditions of 2-substituted imidazole 486 with various... 

An intermolecular approach to carbazoles 273 was reported via an inverse electron-demand Diels-Alder reaction between 3-chloroindoles 271 and pyrones 272. This reaction proceeds through a thermally induced Diels-Alder, decarboxylation, elimination-domino process. Heating the two components under microwave irradiation generates carbazoles with methyl esters in the 3-position in a completely regioselective manner (140L1124). 

Et2AlCl has been extensively used as a Lewis acid catalyst for intermolecular and intramolecular Diels-Alder reactions with a,3-unsaturated ketones and esters as dienophiles. It also catalyzes inverse electron demand Diels-Alder reactions of alkenes with quinone methides and Diels-Alder reactions of aldehydes as enophiles. ... 

The tandem Knoevenagel-Diels-Alder sequence is well known, and has been extensively studied by Tietze and others. The Knoevenagel products have been shown to be active as dienophiles in normal-electron-demand Diels-Alder reactions, as well as heterodienes in inverse-electron-demand hetero-Diels-Alder reactions. One of the most elegant examples of a tandem Knoevenagel-hetero-Diels—Alder sequence is Tietze s synthesis of hirsutine 76. In this sequence, a mixture of aldehyde 70, Meldrum s acid 71, enol ether 73 (a mixture of isomers) and a catalytic amount of ethylenediamine diacetate were sonicated in Benzene for 12 h at 60 °C. This effected a cascade sequence that began with Knoevenagel condensation to form the heterodiene 72, followed by intermolecular hetero-Diels-Alder reaction with enol ether 73 to lead to 74, which underwent in situ hydrolysis and decarboxylation to yield intermediate 75 in 84% yield. 

The Diels-Alder reaction with inverse electron demand has been one of the most intensively studied reactions of 1,2,4-triazines. In this reaction 1,2,4-triazines behave as electron-deficient dienes and react with electron-rich dienophiles to give, generally, pyridines (see Houben-Weyl, Vol. E7b, p 471 ff). [4 + 2] Cycloadditions of 1,2,4-triazines have been observed with alkenes, alkynes, strained double bonds, electron-rich double and triple bonds, but in a few cases also with electron-deficient alkynes C—N double and triple bonds can also be used as dienophiles. In addition to intermolecular Diels-Alder reactions, intramolecular [4 + 2] cycloaddition reactions of 1,2,4-triazines have also been studied and used for the synthesis of condensed heterocyclic systems. A review on the intermolecular Diels-Alder reaction was published by Boger and Weinreb 14 Sauer published a review on his studies in 1992,381 and E. C. Taylor published a summary of his own work on intramolecular Diels-Alder reactions in 1988.382... 

The most extensively studied reaction of 1,2,4-triazines is the Diels-Alder reaction with inverse electron demand, in which the triazines behave as reactive electron-deficient dienes. Electron-rich alkenes and acetylenes have been most often used as dienophiles but alkenes with strained double bonds and nitriles can also react. Besides intermolecular Diels-Alder reactions, which were discussed in detail in CHEC-I, intramolecular cycloadditions have been studied widely and used in the synthesis of condensed heterocyclic systems. A review on intermolecular Diels-Alder reactions was published by Roger and Weinreb in 1987 , Sauer published an account of his studies in 1992 <92BSB52l>, and a summary by Taylor of his own work on intramolecular Diels-Alder reactions was published in 1988 <88BSB599>. 

A strategy developed by Tietze and coworkers early in his independent career involved the application of intramolecular or intermolecular inverse electron demand hetero-Diels-Alder reactions to iridoid total synthesis. The intermolecular [4+ 2]-cycloaddition of ethyl vinyl ether and unsaturated aldehyde 31 provided acetal 32, which underwent double bond isomerization to afford 33 (Scheme 1) An intramolecular variant of this reaction is discussed in detail later (Scheme 10). More recently, Jacobsen and Chavez extended this work with the enantio- and diastereoselective synthesis of a range of iridoid natural products. Utilizing tridentate Cr(III) catalyst 34, acetal 35 was prepared in 98% ee with good diastereoselectivity (Scheme 1)P... 

Metal bis(oxazoline) catalysts are also highly efficient at promoting asymmetric Diels-Alder reactions. Ishira developed a highly selective copper bis(oxazoline) catalyst for use in standard intermolecular Diels-Alder reactions. Arrayas and Carretero used a nickel bis(oxazoline) catalyst in inverse electron demand hetero Diels-Alder reactions of 1-azadienes for the production of functionalized piperidines. bis(oxazoline) catalysts in reactions pyrazolidinone dienophiles and determined that copper and palladium catalysts were most efficient. Sibi applied a copper bis(oxazoline) catalyst in a kinetic resolution experiment in which one enantiomer of dienophile 46 reacts selectively with cyclopentadiene to yield cycloadduct 48 and 98% ee... 

The intramolecular Diels-Alder reaction is most frequently used in natural product total synthesis, and numerous examples will be described in the synthetic utility section. As with the intermolecular variant, intramolecular reactions are highly regioselective and stereoselective and participate in hetero, inverse electron demand, and asymmetric Diels-Alder reactions. One report from 2008 describes the investigation of an intramolecular hetero Diels-Alder reaction in ionic liquids. ... 

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